Download Drug Absorption and Bioavailability

Drug Absorption and
Bioavailability
Juan J.L. Lertora, M.D., Ph.D.
Director
Clinical Pharmacology Program
September 30, 2010
Office of Clinical Research Training and Medical
Education
National Institutes of Health
Clinical Center
GOALS of Drug Absorption and
Bioavailability Lecture
•
•
•
•
Factors Affecting Drug Absorption
Estimation of Bioavailability
Clinical Significance of Differences in
Bioavailability
Prediction of Bioavailability in HighThroughput Drug Candidate Screening
Factors Affecting
DRUG ABSORPTION
• Biopharmaceutic Factors
- Tablet compression
- Coating and Matrix
- Excipients
• Interactions
- Food
- Other Drugs
- Bacteria
• Physiological Factors
1
[PHENYTOIN] µg/mL
Change in PHENYTOIN Excipients
Results in Epidemic Toxicity*
WEEKS
* Bochner F, et al. Proc Aust Assoc Neurol 1973;9:165-70
Factors Affecting
DRUG ABSORPTION
• Biopharmaceutic Factors
• INTERACTIONS
- Food
- Other Drugs
- Bacteria
• Physiologic Factors
ENTERIC METABOLISM OF DIGOXIN*
* Lindenbaum J, et al. N Engl J Med 1981;305:789-94.
2
Factors Affecting
DRUG ABSORPTION
• Biopharmaceutic Factors
• Interactions
• PHYSIOLOGICAL FACTORS
Drug Absorption
Passive Non-Ionic Diffusion:
Primary mechanism for
most drugs.
Drug Absorption
- Specialized Transport Mechanisms
Large Neutral Amino Acid
Transporter:
L-Dopa, Methyldopa, Baclofen
3
Drug Absorption
- Specialized Transport Mechanisms
Oligopeptide Transporter
(PEPT-1):
Amino-beta-lactams
ACE Inhibitors
Drug Absorption
- Specialized Transport Mechanisms
Monocarboxylic Acid
Transporter:
Salicylic acid
Pravastatin
FALLACIES Concerning Gastric Drug
Absorption
• Acidic Drugs absorbed in the stomach
• Basic Drugs absorbed in the small
intestine
• Gastric pH is always acidic
In Fact, most drug absorption occurs in the
SMALL INTESTINE
4
ASPIRIN ABSORPTION FROM
STOMACH AND SMALL INTESTINE*
TABLE 1: ASPIRIN (ASA) ABSORPTION FROM SIMULTANEOUSLY
PERFUSED STOMACH AND SMALL INTESTINE (3)
pH
ASA ABSORPTION
(micromol/100 mg protein/hr)
STOMACH
SMALL BOWEL
ASA SERUM LEVEL
(mg/100 ml)
3.5
346
469
20.6
6.5
0
424
19.7
* From: Hollander D, et al. J Lab Clin Med 1981;98:591-8
Variation in Gastric and Intestinal
pH*
* Meldrum SJ, et al. Br Med J 1972;2:104-6.
PHYSIOLOGICAL FACTORS
Affecting Drug Absorption
-
Rate of gastric emptying is a major
determinant of initial delay in drug
absorption.
-
Intestinal motility is a determinant of the
extent of drug absorption.
5
PATTERNS OF GASTRIC
MOTOR ACTIVITY
FASTING (Cyclical Pattern < 2 HR)
Phase 1
Phase 2
Phase 3
Phase 4
-
Quiescence
Irregular Contractions
Major Motor Complex Burst
Transition Period
Interdigestive Intestinal Motor Activity in
Humans*
*From: Rees WDW, et al. Dig Dis Sci 1982;27:321-9.
PATTERNS OF GASTRIC
MOTOR ACTIVITY
POST PRANDIAL (Up to 10 hr delay)
- Pylorus constricted
- Antral contractions reduce particle size
6
GI TRANSIT - SUSTAINED-RELEASE
CARBAMAZEPINE FORMULATION*
EXTENT RELEASED
75%
56%
*From: Wilding IR, et al. Br J Clin Pharmacol 1991;32:573-9.
Variation in “Peak” Levels
ACETAMINOPHEN (μg/mL)
ACETAMINOPHEN*
LEVELS MEASURED 1-HOUR POST DOSE
PATIENTS
* Prescott LF. Med Clin N Am 1974;42:907-16.
Gastric Emptying Rate Affects
ACETAMINOPHEN Absorption*
WITH
METOCLOPRAMIDE
ALONE
TROUGH
LEVEL
WITH
PROPANTHELINE
*From: Nimmo J, et al. Br Med J 1973;1:587-9.
7
Factors Affecting RATE and
EXTENT of Drug Absorption
RESERVE LENGTH
RESERVE LENGTH is the anatomical length
over which absorption of a drug can occur
MINUS the length at which absorption is
complete.
Effect of METOCLOPRAMIDE on
Digoxin Absorption*
*From: Manninen V, et al. Lancet 1973;1:398-99.
8
Effect of PROPANTHELINE on
Digoxin Absorption*
*From: Manninen V, et al. Lancet 1973;1:398-99.
Factors Affecting RATE and
EXTENT of Drug Absorption
Normal Intestinal Villi
9
Broad Intestinal Villi in a Patient with
SPRUE
Digoxin Levels in Patients with
INTESTINAL MALABSORPTION*
DOSE FOR BOTH
GROUPS = 0.25 mg/day.
[DIGOXIN] (ng/mL)
URINE D-XYLOSE
EXCRETION (gm/5 hr)
†
CONTROLS
MALABSORPTION
1.3 ± 0.3
0.4 ± 0.3
5–8
†
1.1 – 4.1
NORMAL RANGE
* From: Heizer WD, et al. N Engl J Med 1971;285:257-9.
Factors Affecting RATE and
EXTENT of Drug Absorption
10
P-GLYCOPROTEIN EFFLUX PUMP
INTESTINAL LUMEN
OUT
MEMBRANE
IN
SLIDE COURTESY OF M. GOTTESMAN
BIOAVAILABILITY OF SOME
P-GLYCOPROTEIN SUBSTRATES
> 70% ABSORPTION
30% - 70% ABSORPTION
F
%
DRUG
DRUG
< 30% ABSORPTION
F
%
DRUG
F
%
PHENOBARBITAL
100 DIGOXIN
70
CYCLOSPORINE
28
LEVOFLOXACIN
99
INDINAVIR
65
TACROLIMUS
25
METHADONE
92
CIMETIDINE
60
MORPHINE
24
PHENYTOIN
90
CLARITHROMYCIN
55
VERAPAMIL
22
METHYLPREDNISOLONE
82
ITRACONAZOLE
55
NICARDIPINE
18
TETRACYCLINE
77
AMITRIPTYLINE
48
SIROLIMUS
15
DILTIAZEM
38
SAQUINAVIR
13
ERYTHROMYCIN
35
ATORVASTATIN
12
CHLORPROMAZINE
32
DOXORUBICIN
5
> 70% BIOAVAILABILITY OF SOME
P-GLYCOPROTEIN SUBSTRATES
SYSTEMIC
CIRCULATION
50%
GUT
WALL
100%
SMALL
BOWEL
100%
25%
P-gp
75% NET
ABSORPTION
P-gp
50%
50%
25%
25%
UNABSORBED
EFFECTIVE ABSORBING SURFACE
11
FACTORS AFFECTING RATE AND
EXTENT OF DRUG ABSORPTION
Sites of FIRST-PASS Elimination
• INTESTINAL MUCOSA
CYP Enzymes
P-Glycoprotein
• LIVER
CYP Enzymes
FIRST-PASS METABOLISM
PORTAL
VEIN
12
First-Pass Metabolism
P-Glycoprotein Transport
ALDOSTERONE
MORPHINE*
CYCLOSPORINE*
NORTRIPTYLINE
ISOPROTERENOL
ORGANIC NITRATES
LIDOCAINE
PROPRANOLOL
* Known P-Glycoprotein Substrates
Factors Affecting RATE and
EXTENT of Drug Absorption
GOALS of Drug Absorption and
Bioavailability Lecture
•
•
•
•
Factors Affecting Drug Absorption
ESTIMATION OF BIOAVAILABILITY
Clinical Significance of Differences in
Bioavailability
Prediction of Bioavailability
13
BIOAVAILABILITY
BIOAVAILABILITY is the RELATIVE
AMOUNT (F) of a drug dose that reaches the
systemic circulation unchanged and the RATE
at which this occurs.
Serum Concentration-Time Curve
after a Single Oral Dose
Significance of AUC
dE
dE dt
E
D
CL E
CL
F
C dt
E
CL
C dt
0
E
AUC
14
Calculation of AUC
Trapezoidal Rule
From: Rowland M, Tozer TN. Clinical Pharmacokinetics. p 470.
AUC A > B
BUT IS A BETTER THAN B?
ABSOLUTE Bioavailability
D
% Absorption
IV
AUC
oral
D oral AUC IV
x 100
Comparison here is between an ORAL and
an IV Formulation
15
RELATIVE Bioavailability
D
% Relative B.A.
Ref.
AUC
Test
D Test AUC Ref.
x 100
Comparison here is between
2 ORAL Formulations
IS THE NEW FORMULATION BETTER?
RELATIVE Bioavailability
D
% Relative B.A.
Ref.
AUC
Test
D Test AUC Ref.
x 100
AUC Values have to be
Normalized for Dose
16
ASSESSMENT of Bioavailability
• AUC Estimates can be used to estimate Extent of Drug
Absorption
• Recovery of Parent Drug in Urine can be used to
estimate Extent of Drug Absorption
• How is ABSORPTION RATE assessed?
- TMAX
- Integrated Pharmacokinetic Analysis of Absolute
Bioavailability.
Extent of Absorption from
Renal Excretion of Unchanged Drug
CL
Since : F
D
E and E
CL
F
D
oral
CL
E
CL
E
ER
R
CL
E
R (oral)
and D
CL
IV
R
So : % Absorption
D IV
E R (oral)
D oral
E R (IV)
E
E
R (IV)
R
X 100
ASSESSMENT OF Bioavailability
• AUC Estimates Can Be Used to Estimate Extent of Drug
Absorption.
• Recovery of Parent Drug in Urine Can Be Used to
Estimate Extent of Drug Absorption.
• HOW IS ABSORPTION RATE ASSESSED?
- TMAX
- Integrated Pharmacokinetic Analysis of Absolute
Bioavailability.
17
INTERACTION OF DRUG ABSORPTION
AND DISPOSITION PROCESSES
ABSORPTION
.
DISPOSITION
ABSORPTION
FUNCTION
G(t)
DRUG IN PLASMA
ORAL
DOSE
IV DOSE
*
H(t)
=
X(t)
THE OPERATION OF CONVOLUTION
t
INTEGRAL FORM : X(t)
G (τ)
H (t τ) dτ
0
TIME DOMAIN :
X(t)
G (t) H (t)
SUBSIDIARY EQUATION : x (s)
g (s) h (s)
MODEL Used to Analyze
Kinetics of Drug Absorption
ka is absorption rate
ko is rate of nonabsorptive loss
18
Calculation of Bioavailability from
First-Order Absorption Model
ka
F
ka
ko
Methods for Assessment of
ABSOLUTE BIOAVAILABILITY
• CONVENTIONAL:
IV and ORAL
doses given on two separate occasions.
- Requires two study sessions
- Requires two sets of blood samples
- Assumes no change in disposition parameters between
•
studies
STABLE
ISOTOPE:
.
- One study and set of blood samples
- Special synthesis requirements
- Mass Spectrometer Assay required
NAPA-13C2
19
Simultaneous Administration of
Oral NAPA and IV NAPA-C13*
* From Atkinson AJ Jr, et al. Clin Pharmacol Ther 1989;46:182-9.
MODEL Used to Analyze Oral NAPA
and IV NAPA-C13 Kinetics*
* From Atkinson AJ Jr, et al. Clin Pharmacol Ther 1989;46:182-9.
BIOAVAILABILITY Estimates From Kinetic
Analysis and URINE RECOVERY
20
Factors Affecting RATE and
EXTENT of Drug Absorption
NAPA PK Model After IV Dose
VF
Dose
SPLANCHNIC
VC
CLF PARTLY REFLECTS
SPLANCHNIC BLOOD FLOW
IV
SPACE
VS
CLE
SOMATIC
Relationship Between CLF and
Extent of NAPA Absorption*
% ABSORPTION
95
90
85
80
75
70
R2 = 0.8, p = 0.045
65
0.8
1
1.2
1.4
1.6
1.8
2
CLF (L/min)
* From Atkinson AJ Jr, et al. Clin Pharmacol Ther 1989;46:182-9.
21
THOUGHTS About
Absolute Bioavailability Studies
•
•
Absolute Bioavailability is usually studied in
Healthy Subjects, NOT in the Patient Population
for whom the drug is intended.
The Stable Isotope Method is ideally suited for
studies in Special Populations
(e.g. Pediatrics, Pregnant Women, other)
GOALS of Drug Absorption and
Bioavailability Lecture
•
•
•
•
Factors Affecting Drug Absorption
Estimation of Bioavailability
Clinical Significance of Differences in
Bioavailability
Prediction of Bioavailability
RELATIVE Bioavailability Terms
Bioequivalence: AUC and Cmax within
80% - 125% of reference compound.
Bioinequivalence: Greater difference in
bioavailability.
Therapeutic Equivalence: Similar clinical
effectiveness and safety.
Therapeutic Inequivalence: Important clinical
difference in bioavailability.
22
AUC A > B:
Therapeutic Significance?
AUC A > B: B Ineffective
AUC A > B:
A and B Equally Effective
23
Equal AUC but Different Ka:
B is Ineffective
Equal AUC but Different Ka:
A is Toxic
RELATIVE BIOAVAILABILITY
CONCLUSIONS
• BIOEQUIVALENCE =
THERAPEUTIC EQUIVALENCE
• BIOINEQUIVALENCE NOT NECESSARILY =
THERAPEUTIC INEQUIVALENCE
24
GOALS of Drug Absorption and
Bioavailability Lecture
•
•
•
•
Factors Affecting Drug Absorption
Estimation of Bioavailability
Clinical Significance
PREDICTION of Bioavailability as part of HighThroughput Drug Candidate Screening
WHY DRUG DEVELOPMENT FAILS
• Unsuitable Biopharmaceutical Properties
*
• Unsuitable Clinical Pharmacokinetics
• Pharmacology (PD) Doesn’t Work in Humans
• Unexpected Toxicity is Encountered
*
Ronald E. White, Bristol-Myers Squibb (From Good Ligands to
Good Drugs, AAPS-NIGMS Symposium, February 19-21, 1998)
BIOPHARMACEUTIC DRUG CLASSIFICATION
*
CLASS I:
High Solubility-High Permeability
CLASS II:
Low Solubility-High Permeability
CLASS III:
High Solubility-Low Permeability
CLASS IV:
Low Solubility-Low Permeability
* From:
Amidon GL, et al. Pharm Res 1995;12:413-20
25
Three CRITICAL
Biopharmaceutical Properties
• Drug Solubility Relative to Dose
GOOD = Highest Dose in 250 mL H20, PH 1.0-7.5
• Dissolution Rate of Formulation
GOOD = 85% Dissolution in 15 min
• Intestinal Permeability of Drugs
CORRELATION of Rates of Drug
DISSOLUTION and Oral ABSORPTION
* From Rackley RJ. In Young D, Devane JG, Butler J, eds.
In vitro-in vivo correlations. p. 1-15.
Three CRITICAL
Biopharmaceutical Properties
• Drug Solubility Relative to Dose
• Dissolution Rate of Formulation
• INTESTINAL PERMEABILITY of Drug
26
Bioavailability vs. Jejeunal Permeability*
MEASUREMENT
REQUIRES
REGIONAL
JEJEUNAL
PERFUSION
* From Amidon GL et al. Pharm Res 1995;12:413-20.
Bioavailability vs. Caco-2 Cell Permeability
Papp*
* From Arturson P, Karlsson J. Biochem Biophys Res Commun 1991;175:880-5.
Evaluation of Caco-2 Cell Model
• ADVANTAGES
- In Vitro Method
- Suitable for High-Throughput
• DISADVANTAGES
- Paracellular Permeability
- Drug Metabolizing Enzymes and
Transporters
- No Hepatic First-Pass Metabolism
27
BIOPHARMACEUTIC DRUG CLASSIFICATION
*
CLASS I:
HIGH SOLUBILITY-HIGH PERMEABILITY
- in vitro – in vivo correlation generally good
- but no way to account for 1 st pass metabolism
* From:
Amidon GL, et al. Pharm Res 1995;12:413-20
BIOPHARMACEUTIC DRUG CLASSIFICATION
*
CLASS II:
LOW SOLUBILITY-HIGH PERMEABILITY
- rate of absorption limited by dissolution rate
- in vitro – in vivo correlation tenuous since
many factors may affect dissolution
* From:
Amidon GL, et al. Pharm Res 1995;12:413-20
BIOPHARMACEUTIC DRUG CLASSIFICATION
*
CLASS III:
HIGH SOLUBILITY-LOW PERMEABILITY
- Intestinal reserve length is marginal.
- If dissolution is rapid, bioavailability will
reflect intestinal permeability and transit time.
* From:
Amidon GL, et al. Pharm Res 1995;12:413-20
28
BIOPHARMACEUTIC DRUG CLASSIFICATION
*
CLASS IV:
LOW SOLUBILITY-LOW PERMEABILITY
- in vitro – in vivo correlation poor
- good bioavailability not expected
* From:
Amidon GL, et al. Pharm Res 1995;12:413-20
THE BOTTOM LINE
CLASS I DRUGS:
HIGH SOLUBILITY-HIGH PERMEABILITY
- Preferred as development candidates
- FDA may waive repeat in vivo testing if initial
formulation has good bioavailability*.
*
Waiver of In Vivo Bioavailability and Bioequivalence
Studies for Immediate-Release Solid Oral Dosage
Forms Based on a Biopharmaceutics Classification
System, CDER Guidance for Industry, August 2000.
29